111111
`
`1111111111111111111111111111111111111111111111111111111111111
`USOO7320999B2
`
`(12) United States Patent
`Joshi et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,320,999 B2
`Jan. 22,2008
`
`(54) DIMETHYL FUMARATE FOR THE
`TREATMENT OF MULTIPLE SCLEROSIS
`
`(75)
`
`Inventors: Rajendra Kumar Joshi, ZUrich (CH);
`Hans-Peter Strebel, Muri (CH)
`
`(73) Assignee: Fumapharm AG, Luzern (CH)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.c. 154(b) by 202 days.
`
`(21) Appl. No.: 10/197,077
`
`(22) Filed:
`
`Jul. 17, 2002
`
`(65)
`
`Prior Publication Data
`
`US 2003/0018072 Al
`
`Jan. 23, 2003
`
`Related U.S. Application Data
`
`(62) Division of application No. 09/831,620, filed as appli(cid:173)
`cation No. PCT/EP99/08215 on Oct. 29, 1999, now
`Pat. No. 6,509,376.
`
`(30)
`
`Foreign Application Priority Data
`
`Nov. 19, 1998
`
`(DE)
`
`................................ 198 53 487
`
`(51)
`
`Int. Cl.
`A61K 31122
`(2006.01)
`(52) U.S. Cl. ...................................................... 514/549
`(58) Field of Classification Search ..................... None
`See application file for complete search history.
`
`(56)
`
`References Cited
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`(Continued)
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`OTHER PUBLICATIONS
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`(Continued)
`
`Primary Examiner-Raymond J. Henley, III
`(74) Attorney, Agent, or Firm-Finnegan, Henderson,
`Farabow, Garrett & Dunner, L.L.P.
`
`(57)
`
`ABSTRACT
`
`The present invention relates to the use of certain dialkyl
`fumarates for the preparation of pharmaceutical preparations
`for use in transplantation medicine or for the therapy of
`autoimmune diseases and said compositions in the form of
`micro-tablets or pellets. For this purpose, the dialkyl fuma(cid:173)
`rates may also be used in combination with conventional
`preparations used in transplantation medicine and immuno(cid:173)
`suppressive agents, especially cyclosporines.
`
`18 Claims, No Drawings
`
`Page 1 of 7
`
`

`

`US 7,320,999 B2
`Page 2
`
`FOREIGN PATENT DOCUMENTS
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`WO WO 2006/055871
`
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`
`Page 3 of 7
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`

`

`US 7,320,999 B2
`
`1
`DIMETHYL FUMARATE FOR THE
`TREATMENT OF MULTIPLE SCLEROSIS
`
`REFERENCE TO RELATED APPLICATIONS
`
`2
`innnunological defense reaction of the organism against the
`heteroprotein often results in rejection or dissolution of the
`grafts. In host-verses-graft reactions, different stages may be
`distinguished. Depending on the degree of difference
`between the recipient and the donor, this reaction takes place
`at different speeds so that we speak of an acute, sub-acute or
`chronic reaction. The acute rejection process is accompanied
`by the irreversible loss of the transplant (necrotisation) as a
`result of arteriitis or arteriolitis within 48 hours and caunot
`be influenced by the administration of drugs. The sub-acute
`rejection reaction becomes manifest as a rejection crisis
`from day 12 to month 4 with reversible functional disorders
`as a result of a transplant vasculopathy. Finally, the loss of
`function of the transplant as a result of vascular changes
`15 such as obliterating arteriopathy, which proceeds over weeks
`or years and can practically not be influenced by drugs, is
`termed a chronic rejection reaction.
`Vice-versa, rejection reactions of the transplant against
`the recipient, the so-called graft-versus-host reactions, may
`20 occur when innnunocompetent tissues are transplanted, i.e.
`primarily in bone marrow transplantation. Again, the sever(cid:173)
`ity of the reaction is graded, and substantially similar
`complications
`result as
`in host-versus-graft-reactions,
`namely arteriopathies and necroses.
`To avoid such rejection reactions, i.e. the host-versus-
`graft reaction and the graft-versus-host reaction, transplan(cid:173)
`tation medicine essentially makes use of innnunosuppres(cid:173)
`sion, i.e. a weakening of the normal innnunoresponse. For
`this purpose, anti-lymphocyte sera are often used in com-
`30 bination with corticosteroids and so-called anti-metabolites,
`e.g. purine analogues such as 6-mercaptopurine and thiogua(cid:173)
`nine which affect the nucleic acid and protein synthesis and
`thus prevent cell division and proliferation. This leads to
`suppression of the production of antibodies and the cellular
`35 innnune response. The innnunosuppressive agents used for
`therapy are substances which suppress or weaken the innnu(cid:173)
`noreaction in the body either specifically or non-specifically.
`Non-specific
`innnunosuppressive agents are cytostatic
`agents such as, for example, alkylating agents or antime-
`40 tabolites.
`In addition, active ingredients are known which cause at
`least partial specific innnunosuppression, such as corticos(cid:173)
`teroids, antisera, antibodies FK-506, tacrolimus, mycophe(cid:173)
`nolatemofetil and primarily cyclosporines such as cyclospo(cid:173)
`rine A. As a result of using modem innnunosuppressive
`agents, the most important representatives of which are the
`cyclosporines, especially cyclosporine A, it was possible to
`improve the results of transplantation considerably over the
`last few years. At present, the survival rate after one year is
`50 about 60% for liver transplantations, about 80% for heart
`transplantations and over 90% for kidney transplantations.
`Autoinnnune diseases where the endogenic immune sys(cid:173)
`tem attacks endogenic organs, tissues and cells are compa(cid:173)
`rable to graft-versus-host reactions. These are also medically
`55 undesirable reactions of the innnune system which may be
`treated with innnunosuppressive agents, too.
`The danger in using innnunosuppressive agents lies in
`weakening the body's defense against infectious diseases
`and the increased risk of malignant diseases. Therefore, it is
`60 the object of the invention to provide a pharmaceutical
`preparation to be employed in transplantation medicine
`which may be used to treat, especially to suppress weaken
`and/or alleviate host-versus-graft reactions and graft-versus-
`host reactions, but does not have the above disadvantage.
`It is another object of the invention to provide a pharma(cid:173)
`ceutical preparation which may be employed for treating
`autoinnnune diseases, particularly polyarthritis, multiple
`
`This is a Division of connnonly-owned application Ser.
`No. 09/831,620, filed May 10, 2001, now U.S. Pat. No.
`6,509,376, which is a 371 continuation ofPCT Application
`PCT/EP99108215, filed Oct. 29,1999, the text of which is
`not in English, which PCT Application claims priority on 10
`German Application No. 198 53 487.6, filed Nov. 19, 1998,
`the text of which is not in English.
`
`DESCRIPTION
`
`The present invention relates to the use of dialkyl fuma(cid:173)
`rates for preparing pharmaceutical preparations for use in
`transplantation medicine or the therapy of autoinnnune
`diseases and pharmaceutical preparations in the form of
`micro-tablets or micro-pellets containing dialkyl fumarates.
`On the one hand, therefore, it relates especially to the use
`of dialkyl fumarates for preparing pharmaceutical prepara(cid:173)
`tions for the treatment, reduction or suppression of rejection
`reactions of the transplant by the recipient, i.e. host-versus
`graft reactions, or rejection of the recipient by the transplant, 25
`i.e. graft-versus-host reactions. On the other hand, it relates
`to the use of dialkyl fumarates for preparing pharmaceutical
`preparations for treating autoinnnune diseases such as pol(cid:173)
`yarthritis, multiple sclerosis, juvenile-onset diabetes, Hash(cid:173)
`imoto's thyroiditis, Grave's disease, systemic Lupus erythe(cid:173)
`matodes (SLE), Sjogren's syndrome, pernicious anaemia
`and chronic active (=lupoid) hepatitis.
`Both graft rejection and autoinnnune diseases are based
`on medically undesirable reactions or dysregulation of the
`immune system. Cytokins such as interleukins or tumour
`necrose factor a (TNF-a) are substantial mediators influ(cid:173)
`encing the immune system. In general, both are treated by
`the administration of innnunosuppressive agents such as
`cyclosporine.
`In the overall result, autoinnnune diseases may be defined
`as the failure of the tolerance of endogenic substances or
`antigens. As a rule, this tolerance can be maintained only if
`the antigens keep coming into contact with innnunological
`cells. When this tolerance is lost, autoantibodies are formed,
`i.e. a humoral innnunoresponse against endogenic tissue. 45
`The exact nature of the involvement ofTNF-a is not known.
`Transplantations are tissue or organ transplantations, i.e.
`the transfer of tissues such as cornea, skin, bones (bone
`chips), vessels or fasciae, of organs such as kidney, heart,
`liver, lung, pancreas or intestines, or of individual cells such
`as islet cells, a-cells and liver cells, the kidney having the
`greatest significance as a transplanted organ.
`According to the degree of relationship between the donor
`and the recipient we differentiate between autotransplanta(cid:173)
`tion (transfer to another part of the body of the same
`individual), iso-transplantation (transfer to another, geneti(cid:173)
`cally identical individual) and allogenic transplantation
`(transfer to another individual of the same species). Depend(cid:173)
`ing on the site of origin and transplantation, we further
`differentiate between homotopic transplantation (transfer to
`the same site) and heterotopic transplantation (transfer to a
`different site). The above-mentioned transplantations play
`an important role in modem medicine.
`A major problem in transplantation medicine is graft
`rejection after transplantation of the tissue, organ or cell by 65
`immunological defense reactions of the recipient. Such a
`graft rejection is also called host-versus-graft reaction. The
`
`Page 4 of 7
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`US 7,320,999 B2
`
`4
`
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`sclerosis, juvenile-onset diabetes, Hashimoto's thyroiditis,
`Grave's disease, systemic Lupus erythematodes (SLE),
`Sjogren's syndrome, pernicious anaemia and chronic active
`(=Iupoid) hepatitis, without the disadvantages of immuno(cid:173)
`suppression.
`The object of the invention is achieved by using certain
`dialkyl fumarates for preparing phannaceutical preparations
`for use in transplantation medicine and for the therapy of
`autoimmune diseases and phannaceutical preparations in the 10
`form of micro-tablets and micro-pellets containing these
`dialkyl fumarates. The individual subject matters of the
`invention are characterized in detail in the claims. The
`preparations according to the invention do not contain any
`free fumaric acids per se.
`It is known that phannaceutical preparations which, upon
`biological degradation after administration, enter into the
`citric acid cycle or are part thereof gain increasing thera(cid:173)
`peutic significance---especially when given in high dos(cid:173)
`ages-since they can alleviate or heal diseases caused
`cryptogenetic ally.
`Fumaric acid, for example, inhibits the growth of the
`Ehrlich ascites tumour in mice, reduces the toxic effects of
`mitomycin C and aflatoxin and displays antipsoriatic and
`anti-microbial activity. When administered parenterally,
`transdermally and especially perorally, high dosages of
`fumaric acid or its derivatives known so far such as dihy(cid:173)
`droxyl fumaric acid, fumaramide and fumaronitrile have
`such unacceptably severe side effects and high toxicity that,
`in most cases, such a therapy had to be abandoned in the
`past.
`Surprisingly, investigations carried out by the applicant
`have shown that methyl hydrogen fumarate, a metabolite of
`the dimethyl fumarate, initially increases the endotoxin(cid:173)
`stimulated TNF -u secretion in human mononuclear cells of
`periphere blood (periphere blood mononuclear cells=PBMC
`cells) and in isolated monocytes. In addition, the applicant
`was able to show that fumaric acid has an effect on in vitro
`and in vivo haemagglutination which is comparable to that
`of cyclosporine.
`Surprisingly, it has now been found that dialkyl fumarates
`are advantageous for preparing phannaceutical composi(cid:173)
`tions for use in transplantation medicine and for the therapy
`of autoimmune diseases. This is because compositions con(cid:173)
`taining such dialkyl fumarates surprisingly pennit a positive
`modulation of the immune system in host-versus-graft reac(cid:173)
`tions, graft-versus-host reactions and other autoimmune
`diseases.
`European Patent Application 0188 749 already describes
`fumaric acid derivatives and phannaceutical compositions
`containing the same for the treatment of psoriasis. Phanna(cid:173)
`ceutical compositions for the treatment of psoriasis contain(cid:173)
`ing a mixture of fumaric acid and other fumaric acid
`derivatives are known from DE-A-25 30372. The content of
`free fumaric acid is obligatory for these medicaments.
`DE-A-26 21 214 describes medicaments containing the
`fumaric acid mono ethyl ester and its mineral salts as active
`ingredient for the treatment of psoriasis. The publication
`"Hautarzt (Dermatologist) (1987) 279-285" discusses the
`use of fumaric acid mono ethyl ester salts. Phannaceutical
`preparations containing a mixture of fumaric acid monoalky I
`ester salts and a fumaric acid diester for the treatment of
`psoriasis, psoriatic arthritis, neurodennatitis and enteritis
`regionalis Crohn are known from EP 0312 697 B1.
`Specifically, the object of the invention is achieved by the
`use of one or more dialkyl fumarates of the fonnula
`
`wherein Rl and R2, which may be the same or different,
`independently represent a linear, branched or cyclic, satu(cid:173)
`rated or unsaturated C l _20 alkyl radical which may be
`optionally substituted with halogen (CI, F, I, Br), hydroxy,
`C I4 alkoxy, nitro or cyano for preparing a phannaceutical
`preparation for use in transplantation medicine or for the
`15 therapy of autoimmune diseases.
`The C l _20 alkyl radicals, preferably C l _8 alkyl radicals,
`most preferably C l _5 alkyl radicals are, for example, methyl,
`ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl,
`cyclopentyl, 2-ethyl hexyl, hexyl, cyclohexyl, heptyl, cyclo-
`20 heptyl, octyl, vinyl, allyl, 2-hydroxyethyl, 2 or 3-hydroxy
`propyl, 2-methoxy ethyl, methoxy methyl or 2- or 3-meth(cid:173)
`oxy propyl. Preferably at least one of the radicals Rl or R2
`is Cl_5 alkyl, especially methyl or ethyl. More preferably, Rl
`and R2 are the same or different C l _5 alkyl radicals such as
`methyl, ethyl, n-propyl or t-butyl, methyl and ethyl being
`25 especially preferred. Most preferably, Rl and R2 are identical
`and are methyl or ethyl. Especially preferred are the dim(cid:173)
`ethyl fumarate, methyl ethyl fumarate and diethyl fumarate.
`The dialkyl fumarates to be used according to the inven(cid:173)
`tion are prepared by processes known in the art (see, for
`30 example, EP 0 312 697).
`Preferably, the active ingredients are used for preparing
`oral preparations in the fonn of tablets, micro-tablets, pellets
`or granulates, optionally in capsules or sachets. Preparations
`in the fonn of micro-tablets or pellets, optionally filled in
`35 capsules or sachets are preferred and are also a subject
`matter of the invention. The oral preparations may be
`provided with an enteric coating. Capsules may be soft or
`hard gelatine capsules.
`The dialkyl fumarates used according to the invention
`40 may be used alone or as a mixture of several compounds,
`optionally in combination with the customary carriers and
`excipients. The amounts to be used are selected in such a
`mauner that the preparations obtained contain the active
`ingredient in an amount corresponding to 10 to 300 mg of
`45 fumaric acid.
`Preferred preparations according to the invention contain
`a total amount of 10 to 300 mg of dimethyl fumarate and/or
`diethyl fumarate.
`According to a preferred embodiment, the size or the
`50 mean diameter, respectively, of the pellets or micro-tablets is
`in the range from 300 to 2,000 flm, especially in the range
`of 500 or 1,000 flm.
`In addition to graft-versus-host reactions (see above), the
`following autoimmune diseases to be treated may be named:
`55 polyarthritis, multiple sclerosis, graft-versus-host reactions,
`juvenile-onset diabetes, Hashimoto's thyroiditis, Grave's
`disease, systemic Lupus erythematodes (SLE), Sjogren's
`syndrome, pernicious anaemia and chronic active (lupoid)
`hepatitis. Autoimmune diseases in a wider meaning also
`comprise psoriasis, psoriatic arthritis, neurodermatitis and
`60 enteritis regionalis Crohn.
`In addition to the preparations for peroral administration
`in the fonn of micro-pellets, micro-tablets, capsules (such as
`soft and hard gelatine capsules), granulates and tablets cited
`above, suitable phannaceutical preparations are preparations
`65 for cutaneous and trans dermal administration in the fonn of
`ointments, plasters, lotions or shower preparations and for
`parenteral administration in the fonn of aqueous micro-
`
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`US 7,320,999 B2
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`6
`for preparing solid dispersions in according with the melt
`method and the spray drying method.
`The tablets may be provided with an enteric coating. The
`enteric coating may be applied in a classical coating pan or
`sprayed on or applied in a f1uidised bed apparatus. The tablet
`may also be provided with a film coat.
`
`Example 1
`
`Preparation of Enteric-coated Micro-tablets in
`Capsules Containing 120.0 mg of Dimethyl
`Fumarate, which Corresponds to 96 mg of Fumaric
`Acid
`
`the necessary precautions (breathing mask,
`Taking
`gloves, protective clothing, etc.), 12.000 kg of dimethyl
`fumarate are crushed, mixed and homogenized by means of
`a sieve 800. Then an excipient mixture with the following
`composition is prepared: 17.50 kg of starch derivative
`20 (STA-RX® 1500), 0.30 kg of microcrystalline cellulose
`(Avicel® PH 101),0.75 kg ofPVP (Kollidon® 120),4.00 kg
`of Primogel®, 0.25 kg of colloidal silicic acid (Aerosil®).
`The active ingredient is added to the entire powder mixture,
`mixed, homogenized by means of a sieve 200, processed in
`25 the usual manner with a 2% aqueous solution of polyvidon
`pyrrolidone (Kollidon® K25) to ob